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B-prolymphocytic leukemia (B-PLL) displays unique symptoms. At
least 55% of the lymphocytes in circulating blood have large central
vacuoles. When 15–55% of the cells are prolymphocytes, the diagnosis of
atypical CLL, or transitional CLL/PLL is confirmed. In some CLL-like dis-
eases, the layer of cytoplasm is slightly wider. B-CLL was defined as lym-
phoplasmacytoid immunocytoma in the Kiel classification. According to
theWHO classification, it is a B-CLL variation (compare this with lympho-
plasmacytic leukemia, p. 78). CLL of the T-lymphocytes is rare. The cells
show nuclei with either invaginations or well-defined nucleoli (T-prolym-
phocytic leukemia). The leukemic phase of cutaneous T-cell lymphoma
(CTCL) is known as Sézary syndrome. The cell elements in this syndrome
and T-PLL are similar.
!Fig. 23 CLL. a Extensive proliferation of lymphocytes with densely structured
nuclei and little variation in CLL. Nuclear shadows are frequently seen, a sign of
the fragility of the cells (magnification #400). b Lymphocytes in CLL with typical
coarse chromatin structure and small cytoplasmic layer (enlargement of a section
from 23 a, magnification #1000); only discreet nucleoli may occur. c Slightly
eccentric enlargement of the cytoplasm in the lymphoplasmacytoid variant of
Abnormalities of theWhite Cell Series
Monotonous proliferation of small lymphocytes suggests chro-
nic lymphocytic leukemia (CLL)
Fig. 23 d Proliferation of atypical large lymphocytes (1) with irregularly struc-
tured nucleus, well-defined nucleolus, and wide cytoplasm (atypical CLL or tran-
sitional form CLL/PLL). e Bone marrow cytology in CLL: There is always strong
proliferation of the typical small lymphocytes, which are usually spread out dif-
Table 8 Staging of CLL according to Rai (1975)
Stage Identifying criteria/definition
(Low risk) 0 Lymphocytosis" 15000/µl
Bonemarrow infiltration" 40%
Lymphocytosis and lymphadenopathy
Lymphocytosis and hepatomegaly and/or spleno-
megaly (with or without lymphadenopathy)
(High risk) III Lymphocytosis and anemia (Hb$ 11.0 g/dl) (with or
without lymphadenopathy and/or organomegaly)
IV Lymphocytosis and thrombopenia ($ 100000/µl)
(with or without anemia, lymphadenopathy, or
Table 9 Staging of CLL according to Binet (1981)
Stage Identifying criteria/definition
A Hb" 10.0 g/dl, normal thrombocyte count
$ 3 regions with enlarged lymph nodes
B Hb" 10.0 g/dl, normal thrombocyte count
" 3 regions with enlarged lymph nodes
C Hb$ 10.0 g/dl and/or thrombocyte count$ 100000/µl
independent of the number of affected locations
Characteristics of CLL
Age of onset:Mature adulthood
Clinical presentation: Gradual enlargement of all lymph nodes, usu-
allymoderately enlarged spleen, slow onset of anemia and increasing
susceptibility to infections, later thrombocytopenia
CBC: In all cases absolute lymphocytosis; in the course of the disease
Hb", thrombocytes", immunoglobulin"
Further diagnostics: Lymphocyte surfacemarkers (see pp. 68ff.); bone
marrow (always infiltrated); lymph node histology further clarifies
the diagnosis
Differential diagnosis: (a) Related lymphomas: marker analysis,
lymph node histology; (b) acute leukemia: cell surface marker analy-
sis, cytochemistry, cytogenetics (pp. 88ff.)
Course, therapy: Individually varying, usually fairly indolent course;
in advanced stages or fast progressing disease: moderate chemother-
apy (cell surface marker, see Table 7)
Abnormalities of theWhite Cell Series
Atypical lymphocytes are not part of B-CLL
Fig. 24 Lymphomaof the B-cell and T-cell lineages.a Prevalenceof large lympho-
cyteswithclearlydefinednucleoliandwidecytoplasm:prolymphocytic leukemiaof
theB-cell series (B-PLL).bThepresenceof largeblastic cells (arrow) inCLL suggesta
rare transformation (Richter syndrome). c The rare Sézary syndrome (T-cell lym-
phoma of the skin) is characterized by irregular, indented lymphocytes. d Prolym-
phocytic leukemia of the T-cell series (T-PLL) with indented nuclei and nucleoli
(rare). e Bonemarrow in lymphoplasmacytic immunocytoma: focal or diffuse lym-
phocyte infiltration (e.g., 1), plasmacytoid lymphocytes (e.g., 2) and plasma cells
(e.g., 3). Red cell precursors predominate (e.g., basophilic erythroblasts, arrow).
The pathological staging for CLL is always Ann Arbor stage IV because the
bone marrow is affected. In the classifications of disease activity by Rai
and Binet (analogous to that for leukemic immunocytoma), the transition
between stages is smooth (Tables 8 and 9).
Lymphoplasmacytic Lymphoma
The CBC shows lymphocytes with relatively wide layers of cytoplasm. The
bone marrow contains a mixture of lymphocytes, plasmacytic lympho-
cytes, and plasma cells. In up to 30% of cases paraprotein is secreted, pre-
dominantly monoclonal IgM. This constitutes the classic Waldenström
syndrome (Waldenström macroglobulinemia). The differential diagnosis
may call for exclusion of the rare plasma cell leukemia (see p. 82) and of
lymphoplasmacytoid immunocytoma, which is closely related to CLL (see
p. 74).
! Lymphoplasmacytoid immunocytoma: This is a special form of B-
CLL in which usually only a few precursors migrate into the blood-
stream (a lesser degree of malignancy). A diagnosis may only be
possible on the basis of bone marrow or lymph node analysis.
! Lymphoplasmacytic lymphoma: Few precursors migrate into the
bloodstream (i.e., bone marrow or lymph node analysis is some-
times necessary). There is often secretion of IgM paraprotein,
which can lead to hyperviscosity.
Further diagnostics: Marker analyses in circulating cells, lymph node cy-
tology, bonemarrow cytology and histology, and immunoelectrophoresis.
Plasmacytoma cells migrate into the circulating blood in appreciable
numbers in only 1–2% of all cases of plasma cell leukemia. Therefore, para-
proteins must be analyzed in bone marrow aspirates (p. 82).
Facultative Leukemic Lymphomas
(e.g., Mantle Cell Lymphoma and Follicular Lymphoma)
In all cases of non-Hodgkin lymphoma, the transformed cellsmaymigrate
into the blood stream. This is usually observed in mantle cell lymphoma:
The cells are typically of medium size. On close examination, their nuclei
show loosely structured chromatin and they are lobedwith small indenta-
tions (cleaved cells). Either initially, or,more commonly, during the course
of the disease, a portion of cells becomes larger with relatively enlarged
nuclei (diameter 8–12µm). These larger cells are variably “blastoid.” Lym-
phoid cells also migrate into the blood in stage IV follicular lymphoma.
Abnormalities of theWhite Cell Series
a b
Deep nuclear indentation suggests follicular lymphoma or
mantle cell lymphoma
Fig. 25 Mantle cell lymphoma. a Fine, dense chromatin and small indentations
of the nuclei suggest migration of leukemic mantle cell lymphoma cells into the
blood stream. b Denser chromatin and sharp indentations suggest migration of
follicular lymphoma cells into the blood stream. c Diffuse infiltration of the bone
marrow with polygonal, in some cases indented lymphatic cells in mantle cell
lymphoma. Bone marrow involvement in follicular lymphoma can often only be
demonstrated by histological and cytogenetic studies.
“Monocytoid” cells with a wide layer of only faintly staining cytoplasm
occur in blood in marginal zone lymphadenoma (differential diagnosis:
lymphoplasmacytic immunocytoma).
Lymphoma, Usually with Splenomegaly
(e.g., Hairy Cell Leukemia and Splenic Lymphoma
with Villous Lymphocytes)
Hairy cell leukemia (HCL). In cases of slowly progressive general malaise
with isolated splenomegaly and pancytopenia revealed by CBC (leukocy-
topenia, anemia,